An advanced NSCLC patient with ALK-RNF144A and HIP1-ALK fusions treated with ALK-TKI combination therapy: a case report

Abstract

Background: Anaplastic lymphoma kinase (ALK) rearrangement is one of the most important drivers in non-small cell lung cancer (NSCLC). Despite the effectiveness to canonical 3'-ALK fusions, the clinical efficacy of ALK inhibitors in patients with complex ALK fusions, such as nonreciprocal/reciprocal translocation remains uncertain. Exploring the optimal therapeutic regimens for this subset of patients is of crucial clinical significance.

Case description: We reported a female patient diagnosed with stage IVB lung adenocarcinoma (LUAD) harboring a novel ALK-RNF144A fusion, concurrent with a Huntingtin-interacting protein 1 (HIP1)-ALK fusion and a RB1 loss-of-function variant. The patient sequentially received multiple lines of treatment with ALK-tyrosine kinase inhibitor (TKI), chemotherapy, radiotherapy and ALK-TKI combined with anti-angiogenesis. Disease progression accompanied by a squamous cell carcinoma transformation was indicated after ALK-TKI combined with anti-angiogenesis and both ALK-RNF144A and HIP1-ALK fusions were retained in the tumor. The patient was subsequently treated with a third generation ALK-TKI, lorlatinib, in combination with albumin-bound paclitaxel and anlotinib, and then achieved stable disease. The patient remained on the treatment as of the last follow-up resulting in an overall survival (OS) of more than 18 months.

Conclusions: We have reported an advanced NSCLC patient with a complex nonreciprocal/reciprocal ALK translocation containing a novel ALK-RNF144A fusion, concurrent with a RB1 loss-of-function mutation, who subsequently experienced pathological squamous cell carcinoma transformation. The combined treatment with ALK-TKI, chemotherapy, and anti-angiogenesis demonstrates clinical efficacy and may provide optional therapeutic strategies for this phenotype.

Keywords: Non-small cell lung cancer (NSCLC); case report; combined treatment; nonreciprocal/reciprocal ALK translocation; ring finger protein 144A (RNF144A).

Figure 1

Baseline pathological examination and lung CT of the patient. (A) HE staining of the biopsy specimen showed a poorly differentiated tumor tissue. IHC experiments showed positive expressions of ALK, CK, CK5/6, TTF-1, NapsinA, Ki-67, and negative expression of P40, CD56, Syn, and NUT (×100), revealing an ADC origin of the lung cancer. (B) CT scan before treatment (Aug 2021). The locations of the lesions were marked with red circle. HE, hematoxylin and eosin; IHC, immunohistochemistry; ADC, adenocarcinoma; CT, computed tomography.

Figure 2

Imaging examination, pathological examination and NGS results after first-line treatment with aletinib and palliative local radiotherapy. (A) A CT scan and brain MRI after treatment with alectinib for 4.5 months was administered (Dec 2021). (B) HE staining of the biopsy specimen showed a poorly differentiated tumor tissue. IHC experiments showed positive expressions of ALK, CK7, Villin, Ki-67, CK, and negative expression of CK20, P40, TTF-1, and NapsinA (×100). (C) Coexistence of ALK-RNF144A and HIP1-ALK fusions by NGS in a female patient with lung adenocarcinoma. ALK-RNF144A fusion, with breakpoint positions of ALK at chr2 p23.2 and RNF144A at chr2 p25.1. (D) HIP1-ALK fusion, with breakpoint positions of HIP1 at chr7 q11.23 and ALK at chr2 p23.2. NGS, nest-generation sequencing; CT, computed tomography; MRI, magnetic resonance imaging; HE, hematoxylin and eosin; IHC, immunohistochemistry.

Figure 3

The representative lung CT, brain MRI scans, and pathological examination after second-line treatment. (A) A CT scan after treatment with TGRX-326 for 1.9 months (Feb 2022). The locations of the lesions were marked with red arrow. (B) A CT scan and brain MRI after treatment with pemetrexed + carboplatin + bevacizumab for 3 cycles (May 2022). The locations of the lesions were marked with red circle. (C) A computed tomography scan and brain MRI after treatment with 1 cycle of docetaxel combined + temozolomide (Jun 2022). The locations of the lesions were marked with red circle. (D) A CT scan after treatment with crizotinib + anlotinib cycles for 5.1 months (Nov 2022). The locations of the lesions were marked with red circle. (E) A CT scan after treatment with ensartinib + anlotinib cycles for 3.3 months (Feb 2023). The locations of the lesions were marked with red arrow. (F) HE staining of the biopsy specimen showed a poorly differentiated tumor tissue. IHC experiments showed positive expressions of ALK, P40, Ki-67, CK, CD56, and negative expression of TTF-1, NapsinA, Syn, and SOX10 (×100), revealing a SQC transformation of the lung cancer. (G) A CT scan after treatment with 3 cycles of albumin-bound paclitaxel + lorlatinib + anlotinib (Apr 2023). The locations of the lesions were marked with red arrow. PD, disease progression; SD, stable disease; CT, computed tomography; HE, hematoxylin and eosin; MRI, magnetic resonance imaging; SQC, squamous cell carcinoma; IHC, immunohistochemistry.

Figure 4

The timeline and treatment history of the patient (from Aug 2021 to Apr 2023). TOMO, Tomotherapy; VMAT, volumetric modulated arc therapy; chemo, chemotherapy.